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Epilepsy Research (2008) 80, 77—82 journal homepage: www.elsevier.com/locate/epilepsyres Quality of antiepileptic drugs in Vietnam Tu Luong Mac a, Jean-Michel Gaulier b, Van Tuan Le c, Anh Nhi Vu c, Pierre-Marie Preux a, Voa Ratsimbazafy a,∗ a Institute of Neuroepidemiology and Tropical Neurology (EA3174), Faculty of Medicine and Pharmacy, rue du Docteur Marcland, 87025 Limoges Cedex, France b Department of Pharmacology and Toxicology (EA3838), University Hospital, Limoges, France c Department of Neurology, Faculty of Medicine and Pharmacy, Ho Chi Minh Ville, Viet Nam Received 24 October 2007; received in revised form March 2008; accepted 10 March 2008 Available online 22 April 2008 KEYWORDS Epilepsy; Quality; Anti-epileptic drugs; Vietnam; Carbamazepin; Phenytoin Summary The purpose of this research was to evaluate the quality of anti-epileptic drugs (AEDs) in a central city of South Vietnam A cross-sectional study was conducted in all the outlets for AEDs Out of 33 pharmacies 54% had AEDs Where the drugs were available, 89% of the pharmacies, 10 units were purchased, choosing the cheapest ones The information on the packaging, the galenic form and the aspect of the drug were studied Each sample’s tablet was weighted and was considered satisfactory if it was within ±10% of the average A HPLC method was used for dosing the active ingredient (AI), which was considered satisfactory within ±10% of the theoretical value Eight samples were based on carbamazepin and eight on phenytoin None of the 16 samples collected were past their expiring date Tablets were homogeneous in shape, dimension and color The uniformity of weight was satisfactory but the AI results were alarming for Carbamazepin and more often for Phenytoin Only 35% of the tablets were correctly dosed Because of differences of sensitivities of AEDs to storage conditions, environmental factors (heat, light and humidity) could be responsible for this result Best results were achieved in structures where storage seemed to be better The influence of storage conditions must be further studied to confirm this conclusion © 2008 Elsevier B.V All rights reserved Introduction ∗ Corresponding author Tel.: +33 55 43 58 20; fax: +33 55 43 58 21 E-mail addresses: voa.ratsimbazafy@chu-limoges.fr, voa ratsimbazafy@yahoo.fr (V Ratsimbazafy) Epilepsy in Asia is a public health problem, because of its high prevalence, up to 14.0 per thousand (Mac et al., 2007) on one hand, and the frequency of inferior quality medicines on the other hand The World Health Organization (WHO) defines inferior quality medicine as products whose composition and ingredients not meet the correct scientific specifications and which are consequently ineffective and 0920-1211/$ — see front matter © 2008 Elsevier B.V All rights reserved doi:10.1016/j.eplepsyres.2008.03.006 78 often dangerous for the patient The Food and Drug Administration (FDA), estimates that this problem affects today 10% of the world market (OMS, 2003) According to Pincock in 2003, this is particularly problematic in South East Asian countries A study, which took place between 2000 and 2001, covering four countries in this region including Vietnam, concluded that 38% of the sampled anti-malarial oral drugs contained no active ingredients (Newton et al., 2003) Although studies have been done on quality of medicine in developing countries (DC), anti-epileptic drugs (AEDs) have rarely been evaluated (Laroche et al., 2005; Odermatt et al., 2007) Yet, epilepsy concerns about 50 million people worldwide, 85% of which live in a DC (Reynolds, 2001) Recovery frequently requires taking medication over a long period (Farnarier et al., 2002) The level of confidence patients have in their medication is one of the factors influencing a regular intake of medication This is an important factor in the successful treatment of the disease (Lillian et al., 2003) Confronted with poor quality ineffective medication confidence in the treatment may be lost This poor quality may be encountered at different levels in the circuit of drugs But even if we are talking about drugs belonging to an official circuit, we could still have a quality issue Our objective was to study the quality of AEDs which were found in delivery structures of a city centre in South Vietnam Population and methods This observational study was carried out over a period of months, from 27 February to May 2003, in Long Xuyen (LX) It is an urban district of over 106.82 km2 with 256,799 inhabitants LX is the main city of An Giang’s Province, located in the Mekong Delta, neighboring Cambodia in South Vietnam It is divided into 12 communes and communes, My Binh and My Long, which have a combined surface of 2.67 km2 and 46,159 inhabitants, can be considered as the city centre They were chosen because previous observations indicated that most drug outlets are located in the city centre The Gross Domestic Product per inhabitant in Vietnam ere, 2005), was 8,550,000 Vietnamese Dong (VND) (Minist` about US$ 570 (US$ = 15,000 VND) in 2005 The prevalence of epilepsy in Vietnam was estimated to be about 1.4% (Mori, 2003) Delivery structures The assessment of the geographic availability of AEDs was performed using a census with tourist maps The two communes were divided into 11 areas by using natural limits (river and streets) Each area was then entirely visited and all outlets were registered Any points where medicines were dispensed to patients were considered as a potential outlet for AEDs All the delivery structures in the study communes were visited by the investigator According to the local authorities, 44 pharmacies and 99 drugstores were present in the entire district; these included both public and private outlets The private pharmacies, recognizable thanks to their sign ‘‘Nha Thuoc Tay’’ (which means ‘‘pharmacy’’) are generally a street-level store and small in size Only a qualified pharmacist can run a Nha Thuoc T.L Mac et al Tay Medicines are often displayed in the shop window The ‘‘Public’’ or ‘‘State’’ pharmacies have a sign ‘‘Cong Ty Duoc’’ (which means ‘‘pharmaceutical company’’) Also on street-level, they are larger than the private ones, better built and have air-conditioning A qualified pharmacist is in charge of these outlets Drugstores are identifiable by their ‘‘Day Ly Thuoc Tay’’ sign (which means ‘‘drugs retail’’) The managers are not pharmacists but are qualified to run a drugstore There were also wholesalers at the street level The drugs were not exposed in the shop windows but kept inside the store, in their original paper containers Purchasing samples Every time the outlet had AEDs available, 10 units were purchased If several drugs were available, the cheapest ones were purchased The samples were tested right after the return in France in May 2003 Only the cheapest AED were sampled as the price is a major determinant of accessibility Sample analysis Identification and description The type of packaging (bulk or dosage) as well as the information printed on the packaging (brand name, international non-proprietary name (INN), dosage, batch number, name of manufacturer, expiry date) were noted Regarding to the presentation of the drugs, the galenic form and the color of the drug were noted Uniformity of weight For each sample, the tablets were weighed individually and an average weight was calculated This average was then compared to the individual weight of each tablet previously determined The weight of a tablet was considered satisfactory if it was within ±10% of the sample average weight Assay of active ingredient (AI) carbamazepin and phenytoin AI of collected samples was assayed as following in the Laboratory of Pharmacology and Toxicology of the University Hospital Centre of Limoges (EA3838) Calibration curves preparation A stock solution of carbamazepin or phenytoin was prepared by dissolving 10 mg, either of carbamazepin or free base phenytoin as pure substance, 10 mL of methanol to obtain a g/L solution Calibration points (200, 100 and 50 mg/L) were consecutively prepared by dilutions (1/5, 1/10 and 1/20) of the stock solution in a water/methanol (30/70, v/v) mixture Samples preparation Each tablet was dissolved in a water/methanol (30/70, v/v) mixture using an appropriate dilution in order to obtain a stock solution with the theoretical concentration of g/L This stock solution was placed for 15 in an ultrasonic bath to assess the dissolution Analyzed solutions were then prepared with theoretical concentrations of 200 and 100 mg/L, respectively for carbamazepin and phenytoin Materials and methods The chromatographic separation was performed at room temperature on a Nucleosil C18, 150 × 4, 6, ␮m (MACHEREY-NAGEL, France) using a Model 510 pump (WATERS, Quality of AEDs in Vietnam 79 France) and a mixture of acetonitrile and 0.025 M KH2 PO4 buffer adjusted to pH 2.6 (55:45, v/v) as mobile phase Forty microlitre of each solution were injected (injector type 712 WISP, WATERS, France) and the detection was done at 220 nm using an SPD-6AV (SHIMADZU, France) detector The AI content of each tablet was then evaluated using the corresponding calibration curve The linearity of this method was verified for each compound between 50 and 200 mg/L: the correlation coefficients were typically higher than 0.99 The intra- and inter-assay precision and accuracy were satisfactory, with the mean relative error and coefficient of variation less than 15% Preliminary tests Before assaying the AI dosage of the collected AED samples, the analytical method was tested with phenytoin tablets of French origin Four ‘‘reference’’ tablets with a theoretical AI content of 100 mg were collected from a French pharmacy These tablets were prepared as previously described The four g/L stock solutions were kept at room temperature for 24 h Throughout this period, 100 mg/L solutions were consecutively prepared and analyzed after 1, 3, 4.5 and 24 h Results were considered as acceptable if the values measured remained in the area of 90—110% of the theoretical value throughout the 24 h conservation period Data analysis For each sample the contents of tablet were considered satisfactory if the AI content was within ±10% of the theoretical AI Results There were no drug retails and the 33 pharmacies located in My Binh and My Long represented 75% of the outlets of LX They consisted in 32 private structures and public pharmacy Eighteen of them (54%) had at least one AED type Two pharmacies did not accept to sell any AEDs so we collected samples from 16 (89%) of them One sample was also collected from a wholesaler Seventeen samples were collected overall One sample made of valproic acid was not investigated because of the prolonged release pharmaceutical form The characteristics of these samples are presented in Table Identification and description All the AEDs collected were in tablet form The tablets were uniformly white with no visual distortion in the shape All the AEDs were packaged in blister packs with the exception of the brand names Carbamazepine® 200 mg and Depakine® 200 mg which were packaged in bulk The name, batch Table number and the expiry date were found on all the blister packs Preliminary tests The four stock solutions made from the phenytoin tablets collected in France remained stable during the 24 h of storage: the measured AI concentrations in the assayed solutions prepared at H1, H3, H4.5 and H24 remained between 90 and 110% of the theoretical value Uniformity of weight and the AI content The results of the average weight and AI dosage for the 16 samples are listed in Table Each sample of the brands based on carbamazepin contained at least one tablet with under-dosed AI Regarding the brands based on phenytoin, all eight samples were made up of tablets non-conform to the set criteria: either under or over-dosed Forty-seven of the carbamazepin tablets (i.e 58.7%) and 40 phenytoin tablets (i.e 50.0%) had values lower than expected and 17 phenytoin tablets (i.e 21.2%) had values higher than the set norm Only 35% of the tablets were correctly dosed In the case of Depakine® 200 mg tablets, the AI determinations were not performed as these gastro-resistant tablets could not be analyzed with the used methodology owing to dissolution problems Discussion The purpose of this study was to evaluate the quality of AEDs available in the central cities of LX (My Binh and My Long) Results reflect the quality of the cheapest AEDs available in this region as these were specifically targeted The descriptive analysis showed that all the therapeutic classes of AED collected were in ‘‘tablet’’ form These tablets were homogenous in shape, dimension and color The AEDs in dosage packaging carried printed identification information on the packaging On the other hand, for AEDs packaged in bulk, no information was available once the tablets were removed from the bottle It was not surprising to note that all brands of AED were from foreign sources In 2001, it was found, that the majority of medication consumed in Vietnam (60—80%) was imported (Simonet, 2001) Finally, it was observed that none of the samples had past their expiry date This finding was waited as the pharmacies Sample tablets collected, Long Xuyen district, Vietnam, 2003 Active ingredients Brand name ® Origins Number of structures concerned Number collected Carbamazepin Zep 200 mg Carbamazepine® 200 mg Tegretol® 200 mg India Canada France 1 (1 wholesaler) 10 10 60 Phenytoin Valproate Dihydan® 100 mg Depakine® 200 mg France France (1 state structure) 80 10 Total 17 170 80 Table Results of 16 AEDs samples’ assay, Long Xuyen district, Vietnam, 2003 Sample number Brand name Uniformity of weight AI content Satisfied, N (weight: m ± S.D.) No satisfied, N Satisfied N (AI content: m ± S.D.) Under-dosed N (AI content: m ± S.D.) Over-dosed N (AI content: m ± S.D.) 0 0 0 0 1 6a Carbamazepine® Zep® Tegretol® Tegretol® Tegretol® Tegretol® Tegretol® Tegretol® 10 10 10 10 10 10 10 10 (293 ± mg) (245 ± mg) (280 ± mg) (280 ± mg) (281 ± mg) (280 ± mg) (281 ± mg) (279 ± mg) 0 0 0 0 1 (191.96 ± 4.72 mg) (189.94 ± 6.14 mg) (183.37 mg) (183.47 mg) (189.83 ± 6.32 mg) (186.82 ± 4.38 mg) (189.12 ± 4.83 mg) (147.45 ± 25.55 mg) (166.70 mg) 10 (141.97 ± 23.77 mg) (134.68 ± 30.03 mg) (135.89 ± 24.46 mg) (172.10 mg) (136.44 ± 23.84 mg) (141.33 ± 19.65 mg) 10b 11 12 13 14 15 16 Dihydan® Dihydan® Dihydan® Dihydan® Dihydan® Dihydan® Dihydan® Dihydan® 10 10 10 10 10 10 10 10 (174 ± mg) (177 ± mg) (178 ± mg) (177 ± mg) (177 ± mg) (178 ± mg) (177 ± mg) (177 ± mg) 0 0 0 0 1 (96.83 ± 1.05 mg) (100.03 ± 3.57 mg) (105.06 ± 1.32 mg) (100.11 ± 6.34 mg) (97.07 ± 3.57 mg) (101.64 mg) (100.07 mg) (97.10 ± 5.44 mg) 6 56 Total 160 (82.34 ± 7.07 mg) (72.03 ± 4.11 mg) (75.87 ± 1.32 mg) (75.60 mg) (74.21 ± 8.78 mg) (71.94 ± 7.37 mg) (79.29 ± 9.56 mg) 87 (117.59 ± 5.03 mg) (133.28 ± 18.00 mg) (123.42 ± 9.01 mg) (110.38 mg) (156.03 ± 18.25 mg) (115.24 mg) (111.73 mg) 17 N: number; m: mean; S.D.: standard deviation a Sample collected from a wholesaler b Sample collected from a public pharmacy T.L Mac et al Quality of AEDs in Vietnam tend to work on a ‘just in time’ stock control system (Mac et al., 2006) In each of the AED samples the individual weight of the tablets was found to be stable Results of uniformity of weight test showed no excessive heterogeneity of individual weight Despite the good macroscopic aspect and uniformity of weight of the tablets in each of the AED samples, the AI results were alarming A recent study in Lao (Odermatt et al., 2007) did not find any below standard antiepileptic drugs based on Phenobarbital There is high probability that the storages in the two countries were similar These results might be due to physicochemical characteristics of the drugs Tablets of carbamazepin could lose their effectiveness up to one-third if stored in humid conditions (Anonymous, 1999) Phenytoin must be stored in airtight containers, which is not the case of phenobarbital So these bad results could be explained at least in part by the conditions under which the AEDs were stored Among the drugs containing carbamazepin as active ingredient there were two samples that had good results (90% satisfactory) But the best results were achieved with a sample collected from the wholesaler where the drugs were not exposed in the shop windows, but kept inside the store Concerning the phenytoin samples the best results (70% satisfactory) were obtained for tablets collected from a public pharmacy, which had the particular advantage to have air conditioning The other samples collected were displayed in the shop windows and for the most part, these windows are exposed to the street and are subjected to the local tropical climate The AEDs placed in these windows were therefore overexposed to heat, light and humidity The blister packs offer very little protection (Yang et al., 2004) Subject to such storage conditions the accelerated degradation of the AI is possible Thereto, in 1997, Ballereau et al showed a loss of antiinfectious AI under such conditions This hypothesis was also been put forward by Shakoor et al (1997), to explain the bad results obtained in the same therapeutic class Bad storage conditions could also have an impact on the galenic and dissolution properties of the tablets A dissolution test of the AEDs was not done in this study In 1993, Wang et al showed that carbamazepin tablets that were subjected to heat and humidity, dissolved badly And Yang et al in 2004 showed similar results for aspirin tablets collected from drugstores in Cambodia Bad dissolution of the tablets could also have an impact on the AI dosage In fact, the AI of the AEDs is put into a solution before dosing The AI in this solution might not dissolve completely which would explain the variable results obtained in this study It should be noted here however that a study directed by Risha et al (2003), on medications other than AEDs, showed acceptable levels of AI content despite such dissolution problems A hypothesis of counterfeit tablets such as in the case of anti-malarial drugs in Vietnam (Newton et al., 2001) is less likely An extremely low, or absent AI content is usually the sign of counterfeiting (Taylor et al., 2001) Although our study found most of the AI content to be outside the set limits it was not excessively so According to Petralanda in 1995, the variability of AI content in tablets could also simply be due to bad manufacturing practices 81 Compared to the study done by Laroche et al (2005) which presented far more acceptable results on the quality of phenobarbital in Mauritania (sub-Saharan Africa), our study reflected far more worrying results Whereas phenobarbital is a recommended first line drug and seems to be much more resistant to degradation in stock, because of extra-therapeutical overuse in Vietnam, it was only present in hospital structures In conclusion, even if we did not investigate this issue, photo, aqua and thermoinduced degradations of the AI, as well as a probable modification of the dissolution properties of the medication are plausible reasons for the results observed in this study In the future, investigations must be done to confirm this hypothesis Improvement of the quality of AEDs in DC is important because epilepsy concerns a lot of people in these countries and requires taking medication over a long period This study carried on AEDs belonging to an official circuit in a city centre of a district of South Vietnam shows that a particular attention should be paid on the storage conditions of drugs in developing countries This would be obtained through actions making aware of this issue both pharmacy’s workers and patients and via labels shouting out, which labels should be maintained on drug’s package until patients take the AED Acknowledgements We thank ‘‘l’Ecole Doctorale Sciences-Technologies-Sant´ e’’ of the University of Limoges, the ‘‘Conseil R´ egional du Limousin’’, Bernard Bouteille, Bernard Penicaut, Jean-Marie Baronnet, Van Phuoc Dang, Thi Xuan Le Le, Chi Cong Nguyen, Thi Nhat Mai Pham for their help in preparing and writing this paper We declare that the experiments comply with the current laws of Vietnam in which they were performed inclusive of ethics approval References Anonymous, 1999 Antiepileptics In: Martindale, The Complete Drug Reference, 32nd ed Pharmaceutical Press, London, UK, p 339, 350, 352 Ballereau, F., Prazuck, T., Schrive, I., Lafleuriel, M.T., Rozec, D., Fisch, A., Lafaix, C., 1997 Stability of essential drugs in the field: results of a study conducted over a two-year period in Burkina Faso Am J Trop Med Hyg 57, 31—36 Farnarier, G., Nimaga, K., Desplats, D., Doumbo, O., 2002 Traite´pileptiques en milieu rural au Mali Rev Neurol., ment des e 158 Laroche, M.L., Traore, H., Merle, L., Gaulier, J.M., Viana, M., Preux, P.M., 2005 Quality of phenobarbital solid-dosage forms in the urban community of Nouakchott (Mauritania) Epilepsia 46, 1293—1296 Lillian, L., Chun-Hing, Y., Der-Jen, Y., Mei-Huei, C., Ming-Fang, L., 2003 Medication education for patients with epilepsy in Taiwan Seizure 12, 473—477 Mac, T.L., Le, V.T., Vu, A.N., Preux, P.M., Ratsimbazafy, V., 2006 AEDs availability and professional practices in delivery outlets in a city centre in southern Vietnam Epilepsia 47, 330—334 Mac, T.L., Tran, D.S., Quet, F., Odermatt, P., Preux, P.M., Chong, T.T., 2007 Epidemiology, aetiology, and clinical management of epilepsy in Asia: a systematic review Lancet Neurol 6, 533—543 82 Minist` ere de l’´ economie, 2005 des finances et de l’industrie, ´conomique Direction g´ en´ erale du tr´ esor et de la politique e ´conomiques, Statistiques Les publications des missions e ´conomiques, Vietnam, Mai 2005 [Article online] Available from e http://www.missioneco.org/vietnam/documents new.asp?V=1 PDF 105420 (accessed February 17, 2006) Mori, P., 2003 Combattre l’´ epilepsie au Vietnam Pulsations 4, 10 Newton, P., Proux, S., Green, M., et al., 2001 Fake artesunate in Southeast Asia Lancet 357, 1948—1950 Newton, P.N., Dondorp, A., Green, M., Mayxay, M., White, N.J., 2003 Counterfeit artesunate antimalarials in Southeast Asia Lancet 362, 169 Odermatt, P., Ly, S., Simmala, C., Angerth, T., Phongsamouth, V., Mac, T.L., Ratsimbazafy, V., Gaulier, J.M., Strobel, M., Preux, P.M., 2007 Availability and costs of antiepileptic drugs and quality of Phenobarbital in Vientiane municipality, Lao PDR Neuroepidemiology 28 (3), 169—174 Organisation Mondiale de la Sant´ e, 2003 M´ edicaments de qualit´ e inf´ erieure et contrefaits Available from http://www.who.int/ mediacentre/factsheets/fs275/fr/ (accessed September 26, 2005) Petralanda, I., 1995 Quality of antimalarial drugs and resistance to Plasmodium vivax in Amazonian region Lancet 346, 122 Pincock, S., 2003 WHO tries to tackle problem of counterfeit medicines in Asia BMJ 327, 1126 T.L Mac et al Reynolds, E.H., 2001 ILAE/IBE/WHO global campaign ‘‘out of the shadows’’: global and regional developments Epilepsia 42, 1094—1100 Risha, P.G., Vervaet, C., Vergote, G., Bortel, L.V., Remon, J.P., 2003 Drug formulations intended for the global market should be tested for stability under tropical climatic conditions Eur J Clin Pharmacol 59, 135—141 Shakoor, O., Taylor, R.B., Behrens, R.H., 1997 Assessment of the incidence of substandard drugs in developing countries Trop Med Int Health 2, 839—845 Simonet, D., 2001 Une analyse du march´ e pharmaceutique vietnamien Cahiers sant´ e 11, 155—160 Taylor, R.B., Shakoor, O., Behrens, R.H., Everard, M., Low, A.S., Wangboonskul, J., Reid, R.G., Kolawole, J.A., 2001 Pharmacopoeial quality of drugs supplied by Nigerian pharmacies Lancet 357, 1933—1936 Wang, J.T., Shiu, G.K., Ong-Chen, T., Viswanathan, C.T., Skelly, J.P., 1993 Effects of humidity and temperature on in vitro dissolution of carbamazepine tablets J Pharm Sci 82, 1002— 1005 Yang, D., Plianbangchang, P., Visavarungroj, N., Rujivipat, S., 2004 Quality of pharmaceutical items available from drugstores in Phnom Penh, Cambodia Southeast Asian J Trop Med Public Health 35, 741—747 ... if it was within ±10% of the sample average weight Assay of active ingredient (AI) carbamazepin and phenytoin AI of collected samples was assayed as following in the Laboratory of Pharmacology... medication confidence in the treatment may be lost This poor quality may be encountered at different levels in the circuit of drugs But even if we are talking about drugs belonging to an official circuit,... to run a drugstore There were also wholesalers at the street level The drugs were not exposed in the shop windows but kept inside the store, in their original paper containers Purchasing samples

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